MXPA02008536A - Dihydro 2h naphthalene 1 one inhibitors of ras farnesyl transferase. - Google Patents

Abstract

The present invention provides dihydro 2H napthalene 1 ones and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, which are useful for treating and preventing uncontrolled or abnormal proliferation of tissues, such as cancer, atherosclerosis, restenosis, and psoriasis. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme.

Description

INHIBITORS DIHYDRO-2H-NAFTALEN-1 -ONE OF RAS FARN ESIL TRANSFERASA FIELD OF THE INVENTION The present invention relates to compounds that can be used to treat, prophylactically or otherwise, uncontrolled or abnormal tissue proliferation. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme, which has been determined to activate ras proteins which in turn activate cell division and are implicated in cancer, restenosis and atherosclerosis.

COMPENDIUM OF THE RELATED TECHNIQUE The protein Ras (or p21) has been examined extensively because its mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs, J. B., Ce / 7, 1991; 65: 1, Cartwright T. et al. , Chimica. Oggi. , 1992; 10:26). These mutant ras proteins are deficient in the capacity for feedback regulation that occurs in native ras, and this deficiency is associated with its oncogenic action from the ability to stimulate normal cell division that can not be controlled by endogenous regulatory cofactors. normal. The recent discovery that mutant ras transformation activity is critically dependent on modifications post-translation (Gibbs J. et al., Microbiol. Rev., 1989; 53: 171) has revealed an important aspect of ras function and identified novel prospects for cancer therapy. In addition to cancer, there are other conditions of uncontrolled cell proliferation that may be related to excessive expression and / or function of native ras proteins. Post-surgical vascular restenosis and atherosclerosis are such conditions. The use of various surgical revascularization techniques such as saphenous vein bypass graft, endarterectomy, and transluminal coronary angioplasty are often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and proto-oncogenes have been implicated (Naftilan AJ et al., Hypertension, 1989; 1 3: 706 and J. Clin. Invest., 1989, 83: 1419; Gibbons GH et al., Hypertension, 1989; 14: 358; Satoh T. et al., Molec., Cell. Biol., 1993; 13: 3706). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells divide uncontrollably. In the direct analogy to the inhibition of cancer related to ras mutants, the blockade of ras-dependent processes has the potential to reduce or eliminate the proliferation of inappropriate tissue associated with restenosis or atherosclerosis, particularly in those cases in which where the expression of normal ras and / or function is exaggerated by the growth stimulating factors. See, for example, Kohl et al. , Nature Med., 1995; 1 (8): 792-797. The ras function is dependent on the modification of the proteins to associate with the internal face of the plasma membranes. Different membrane associated proteins, ras proteins that lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a soluble cytosol form. The ras protein membrane association is driven by a series of post-translational processing steps that are signaled by a carboxyl-terminal amino acid consensus sequence that is recognized by farnesyl transferase protein (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids, and the C terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesyl pyrophosphate in a reaction that is catalyzed by protein farnesyl transferase. Following prenylation, the three terminal amino acids C are split by an endoprotease and the newly exposed alpha-carboxyl group of the prize cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that start with farnesylation allows the protein to associate with the cell membrane. The mutant analysis of the oncogenic ras proteins indicates that these post-translational modifications are essential for the transformation activity. The replacement of the cysteine residue of consensus sequence with other amino acids gives a ras protein that is not farnesylated greatly, fails to migrate to the cell membrane, and loses the ability to stimulate cell proliferation (Hancock JF, et al., Cell, 1989; 57: 1617; Schafer WR et al., Science, 1989; 245: 379; Casey PJ, Proc. Nati, Acad. Sci. USA, 1989; 86: 8323). Recently, PFTs, also referred to as farnesyl transferase proteins (FPT), have been identified and a specific PFT from the rat brain is purified to homogeneity (Reiss, Y. et al., Bioch. Soc. Trans., 1992; 20: 487-88). The enzyme is characterized as a heterodimer composed of an alpha subunit (49kDa) and a beta subunit (46kDa), both of which are required for catalytic activity. Expression levels of mammalian TFP in a baculovirus system and purification of the recombinant enzyme in active form have also been carried out (Chen W.-J. et al., J. Biol. Chem., 1993; 268: 9675) . In light of the above, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through the inhibition of processing enzymes. The identification and isolation of a PFT that catalyzes the addition of a farnesil group to the ras proteins provides a promising goal for such intervention. Ras rasnesyl transferase inhibitors have been shown to have anti-cancer activity in several recent articles. Ris inhibiting agents act to inhibit farnesyl transferase, the enzyme responsible for the posttranslation modification of ras protein that helps to bind the ras gene product to the cell membrane. The role of the ras mutation in the transduction growth signals within the cancer cells is relying on the protein that is in the cell membrane. The inhibition of farnesyl transferase will result in the ras protein remaining in the cytosol and, consequently, being unable to transmit growth signals. These facts are well known in the literature. A peptidomimetic inhibitor of farnesyl transferase B956 and its methyl ester B1086 at 100 mg / kg has been shown to inhibit tumor growth by human bladder carcinoma EJ-1, human fibrosarcoma HT1080, and human colon carcinoma xenografts in nude mice (Nagasu T. et al., Cancer Res., 1995; 55: 5310-5314). In addition, the inhibition of tumor growth by B956 has been shown to correlate with the inhibition of ras post-translational processing in the tumor. Other inhibitors of ras farnesyl transferase have been shown to specifically avoid ras processing and membrane location and are effective in reversing the transformed phenotype of cells containing mutant ras (Sepp-Lorenzino L., et al., Cancer Res., 1995; 55: 5302-5309). In another report (Sun J. et al., Cancer Res., 1995; 55: 4243-4247), an FTI276 ras farnesyl transferase inhibitor has been shown to selectively block tumor growth in nude mice of human lung carcinoma with mutation. K-ras and suppression p53. In yet another report, the daily administration of a farnesyl transferase ras inhibitor L-744,832 causes tumor regression of mammary and salivary carcinomas in ras transgenic mice (Kohl et al., Nature Med., 1995; 1 (8): 748 -792). Thus, ras farnesyl transferase inhibitors have benefits in certain forms of cancer, particularly those dependent on oncogenic ras for their growth. It is well known, however, that human cancer often manifests when several mutations in important genes occur, one or more of whose mutations may be responsible for controlling the growth and metastasis. A single mutation may not be enough to sustain growth, but after the occurrence of only two out of three mutations, tumors can develop and grow. It is difficult, however, to determine which of these mutations can lead primarily to growth in a particular type of cancer. Thus, ras farnesyl transferase inhibitors may have therapeutic utility in tumors not only dependent on oncogenic forms of ras for their growth. For example, it has showed that several FT ras inhibitors have antiproliferative effects in vivo against tumor lines with either wild type or ras mutant (Sepp-Lorenzino, supra.). In addition, there are several ras related proteins that are prenylated. Proteins such as R-Ras2 / TC21 are ras-related proteins that are prenylated in vivo by farnesyl transferase and geranylgeranyl transferase I (Carboni et al., Oncogene, 1995; 10: 1905-1913). Therefore, ras farnesyl transferase inhibitors could also block the prenylation of the above proteins and, therefore, could then be useful for inhibiting the growth of tumors directed by other oncogenes. With respect to restenosis and vascular proliferative diseases, it has been shown that the inhibition of cellular ras prevents the proliferation of smooth muscle after vascular damage in vivo (Indolfi C, et al., Nature Med., 1995; 1 (6): 541-545). This report definitely supports a role for farnesyl transferase inhibitors in this disease, showing inhibition of vascular smooth muscle accumulation and proliferation.

SUMMARY OF THE INVENTION This invention provides novel dihydro-2H-naphthalen-1 -ones which are useful for treating and preventing uncontrolled or abnormal proliferation of tissues, such as cancer, atherosclerosis, restenosis, psoriasis and endometriosis. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme. The compounds also inhibit amyloidosis, and are thus useful for treating conditions caused by amyloidosis, such as Alzheimer's disease. The compounds are readily synthesized and can be administered to mammals by a variety of routes, including orally and parenterally, and have little or no toxicity. The present invention provides a compound of Formula V and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: Ra, Rb and R ° are independently hydrogen, Ci-Cß alkyl, C 2 -C β alkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl , heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2l NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mP? 3 (alkyl) 2 > - (CH2) mS02NH2, and - (CH) mSO2NH- alkyl, wherein m is 0, 1, 2 or 3; R1 and R2 are independently hydrogen, C.sub.2 -C.sub.2 alkyl, C.sub.2 -C.sub.6 alkenyl, aryl, heteroaryl, aryalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups selected independently of the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2 ) mSO2NH2, - (CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2) S-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3, and wherein each of the groups R1 and R2 can be joined through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of OOO -NHC-, -CNH, -CO-, S, SO, SO2, O and NR °; And it's NRC, O, -CHRC, or S; n is 0, 2 or 3, with the proviso that when the imidazole is bound to the imidazole nitrogen a (CRaRb) n and Y is O, NR ° or S, then n is not 0; Y R is aryl, heteroarylalkyl, or arylalkyl, wherein the aryl, heteroaryl or arylalkyl is optionally substituted with up to three groups selected from the group consisting of halogen, C.sub.-C.sub.be alkyl, amino, C.sub.C.sub.bexy, hydroxy, trifluoromethyl, mono- or dialkylamino, Ci-Cβ thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C? -C6, (CH2) mCO2H, (CH2) mC? 2alkyl of d-C6, (CH2) mSO3H , - (CH2) mPO3H2, (CH2) mPO3 [d-Cß alkyl. (CH2) mSO2NH2l and (CH2) mSO2NHalkyl of C? -C6, wherein m is 0, 1, 2 or 3. The present invention also provides a compound of Formula VI and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R1 and R2 are independently hydrogen, alkyl Ci-Cβ, C2-C6 alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3lNO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mC02H, - (CH2) mC02-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mP03H2, - (CH2) mP03 (alkyl) 2l - (CH2) mS02NH2, - (CH2) m -heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mS02-aryl, - (CH2) mS02-heteroaryl, and - (CH2) mS02NH-alkyl, wherein m is 0, 1, 2 or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such a linker selected from the group consisting of OO O -NHC-, -CNH, -CO-, S, SO, SO2, O and NRC; R ° is hydrogen, alkyl (C.-Cß), or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, Ci-Cß alkyl, amino, Ci-Ce alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C? -C6, (CH2) mCO2H, (CH) mCO2alkyl of d-C6, (CH2) mSO3H, - (CH2) mPO3H2 , (CH2) mPO3 [(d-C6 alkyl), (CH2) mS? 2NH2, and (CH2) S? 2NHalkyl of C? -C6, wherein m is 0, 1, 2 or 3; Y R is aryl, heteroarylalkyl or arylalkyl, wherein the aryl, heteroaryl or arylalkyl is optionally substituted with up to three groups selected from the group consisting of halogen, Ci-Cβ alkyl, amino, C.-Cβ alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanil, NHCOalkyl of C.-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of d-Cßl (CH2) mSO3H, - (CH2 ) mPO3H2, (CH2) mPO3 [C? -C6 alkyl] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C.-C6, wherein m is 0, 1, 2 or 3. Additionally, the present invention provides a compound of Formula VIII and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R1 and R2 are independently hydrogen, alkyl C-i-Cβ, C2-C6 alkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl , - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m-heteoaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mS02NH-alkyl, wherein m is 0, 1, 2, or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such a linker selected from the group consisting of OO O -NHC-, -CNH, -CO-, S, SO, SO2, O and NRC; Rc is hydrogen, Ci-Cß alkyl, or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, C-Cβ alkyl, amino, d-Cβ alkoxy, hydroxy, trifluoromethyl, mono or dialkylamino, thioalkoxy of C.-C6, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of d-C6, (CH2) mSO3H, - (CH2) mPO3H2 , (CH2) mPO3 [d-C6 alkyl] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of d-Cß, wherein m is 0, 1, 2 or 3; Y R is aryl optionally substituted with up to three groups selected from the group consisting of halogen, C-Cβ alkyl, amine, C.-Cβ alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, C.-Cß thioalkoxy, cyano , nitro, 1,3-dioxolanyl, NHCOalkyl of d-C6l (CH2) mC02H, (CH2) mCO2alkyl of d-C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C -CS alkyl] , (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C.-Cß, wherein m is 0, 1, 203; In addition, the present invention provides a compound of Formula VIII and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R1 and R2 are independently hydrogen, alkyl C.-Cβ, C2-Cβ alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - ( CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of OO O -NHC-, -CNH, -CO-, S, SO, S02, O and NRC; R ° is hydrogen, d-Cß alkyl, or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl, or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, C-Ce alkyl, amino, Ci-Cβ alkoxy, hydroxy, trifluoromethyl, mono - or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-Cß, (CH 2) mCO 2 H, (CH 2) mC 2 (C 6 -C 6) alkyl, (CH 2) ) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [d-C6 alkyl] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C? -C6, wherein m is 0, 1, 2 or 3; Y R5 is aryl optionally substituted with up to three groups selected from the group consisting of halogen, C, -C, alkyl, amino, Ci-C, alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, C, -C, thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of d-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of C? -C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C? Cß] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of dC6, wherein m is 0, 1, 2 or 3. The present invention also provides a compound of Formula IX and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R 2 is hydrogen, C 1 -C 7 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with a group selected independently from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mS? 2NH2, - (CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyio, wherein m is 0, 1, 2 or 3, and wherein each of the groups R1 and R2 can be joined through a linker, or through a lower alkyl optionally interrupted by a linker, such a linker selected from the group consisting of OOO -NHC-, -CNH, -CO-, S, SO, SO2, O and NH; R 4 is hydrogen or phenyl; and R5 is aryl optionally substituted by Ci-Cß alkyl, C.-Cβ alkoxy or cyano. Additionally, the present invention provides a compound of Formula X X and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R 2 is hydrogen, Ci-Cβ alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with a group independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen , 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) ". PO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2 ) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3, and wherein each of the groups R1 and R2 can be joined through a linker, or through a lower alkyl optionally interrupted by a linker, such a linker selected from the group consisting of OOO -NHC-, -CNH, -CO-, S, SO, S02, O and NH; R 4 is hydrogen or phenyl; and R5 is aryl optionally substituted by Ci-Cß alkyl, C.-Cβ alkoxy, or cyano. The present invention also provides a pharmaceutically acceptable composition comprising a composed of Formulas I-X and a pharmaceutically acceptable carrier. Additionally, the present invention provides a pharmaceutical composition comprising a compound of the Formulas I-X and a pharmaceutically acceptable carrier, excipient or diluent. The present invention also provides a method for treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis is a therapeutically effective amount of a compound of Formulas I-X. The present invention also provides a method for treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of the formulas l-X. In a preferred embodiment of the method of treating cancer, the cancer is lung, colon, pancreatic, thyroid, or bladder cancer. The present invention also provides a method for treating atherosclerosis, the method comprising administering to a patient having atherosclerosis a therapeutically effective amount of a compound of the formula I-X. Also provided is a method for treating or preventing restenosis or atherosclerosis or treating cancer, the method comprises administering to a patient having restenosis or atherosclerosis, or the danger of having restenosis or atherosclerosis, or having cancer a therapeutically effective amount of a compound of the formulas I-X. In addition, the present invention provides a use of a compound of the Formulas I-X, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing any of the diseases or disease states mentioned above.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds encompassed by the present invention are those described by the general formulas V-X set forth above, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof. In addition to the compounds of Formulas V-X, the present invention encompasses compounds of Formulas I-IV. The compounds of the invention are members of the class of compounds of Formula I: wherein: Ra, R, and Rc independently are hydrogen, C-alkyl. -Cß, alkene of C2-Cß, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; or R1 'and R2' independently are hydrogen, Ci-Cß alkyl, C 2 -C β alkenyl, aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein each of the above groups can be linked directly through a linker, or through a lower alkyl group, such alkyl group optionally being interrupted by a linker, such linker selected from OO -NHC-, -CNH, S, SO, SO2, O and NRC '; n 'is 0, 2, or 3, with the proviso that when the imidazole is bound to the imidazole nitrogen a (CRa Rb) n, and Y' is O, NRC or S, then n is not 0; Y 'is NR0', O, CHR0 ', or S; and R3 'is aryl, heteroarylalkyl, or arylalkyl wherein each ring is optionally independently substituted with up to three groups selected from halogen, Ci-Cß alkyl, amino, C.sub.-Cβ alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino , thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCO alkyl of C.-C6, (CH2) m'CO2H, (CH2) m'CO2 alkyl of C.-Cß, (CH2) m 'SO3H, - (CH2) m'PO3H2, (CH2) m'PO3 (d-C6 alkyl) 2, (CH2) m'SO2NH2, and (CH2) m'SO2NH C? -C6 alkyl wherein m 'is 0, 1, 2 or 3. Preferred compounds of Formula I are those wherein R1 is hydrogen; R2 'is hydrogen, lower alkyl, arylalkyl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl, phenylsulfonylalkyl, or alkoxycarbonylalkyl; Cast; Ra 'is hydrogen; R 'is hydrogen, aryl or substituted aryl; n 'is 2; and R3 'is benzyl or substituted benzyl. In addition to the compounds of Formula I, the invention encompasses compounds of Formula II: wherein R1 ', R2 and R3 are as defined above by Formula I; q 'is 1 or 2; and R4 'is hydrogen, aryl, heteroaryl or substituted aryl. Preferred compounds of Formula II are those in which R 1 is hydrogen; R 2 is hydrogen, lower alkyl, arylalkyl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl, phenylsulfonylalkyl, or alkoxycarbonylalkyl; q 'is 1; R 4 is hydrogen, pyridyl, or phenyl; and R3 is benzyl or substituted benzyl.

Most preferred compounds of Formula II are when R .2 'is in position 5. In addition to the compounds of Formula I, the invention encompasses compounds of Formula III: wherein q ', R1', R2 'and R4 are as defined above for Formulas I and II, and R5 is aryl or substituted aryl. The preferred compounds of Formula III are where q 'is 1; R1 is hydrogen; R 2 is hydrogen, lower alkyl, lower alkyl sulfonylalkyl, arylalkyl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl, phenylsulfonylalkyl, heteroarylsulfonylalkyl, or alkoxycarbonylalkyl; R4 'is hydrogen, pyridyl or phenyl; and R5 'is phenyl or substituted phenyl. The most preferred compounds of Formula III are where R2 'is in the 5-position. In addition to the compounds of Formula I, the invention encompasses compounds of Formula IV: wherein q ', R1', R2 and R4 are as defined above for Formulas I and I I, and R5 is aryl or substituted aryl. The preferred compounds of Formula IV are where q 'is 1; R1 'is hydrogen; R2 'is hydrogen, lower alkyl, lower alkyl sulfonylalkyl, arylalkyl, heteroarylalkyl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl, phenylsulfonylalkyl, heteroarylsulfonylalkyl or alkoxycarbonyllalkyl; R4 'is hydrogen, pyridyl or phenyl; and R5 'is phenyl or substituted phenyl. The most preferred compounds of Formula IV are where R2 is in the 5-position. The terms "alkyl", "lower alkyl" or "Ci-Ce alkyl" mean a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexylo and the like. The alkyl group can also substituted with one or more of the substituents listed below for aryl. The terms "alkenyl", "lower alkenyl" or "C2-Cß alkenyl" mean a straight or branched hydrocarbon having from 2 to 6 carbon atoms and 1 or 2 double bonds, and includes, for example, aiyl, 3- methyl-but-2-enyl, 2-methyl-but-2-enyl, geran? lo, and the like. The term "C2-Cß alkenyl" includes within its definition the term "C2-C2 alkenyl.". The alkenyl group can also be substituted with one or more of the substituents listed later by aryl. The term "cycloalkyl" means a saturated hydrocarbon ring containing from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. By "alkoxy", "lower alkoxy" or "C. -C.sub.be alkoxy" in the present invention is meant straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy , Sopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy. The term "aryl" means an unsubstituted aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings in which at least one is aromatic (e.g. , 2,3,4-tetrahydronaphthyl, naphthyl, anthryl or fenantri lo). The term "substituted ary" means an ary substituted by 1 to 3 substituents selected from alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, N H2, N HCH3, N (CH3) 2, NHCO-alkylo, - (CH2) mCO2H, - (C H2) mCO2-alkylo, - (CH2) mSO3H, -NH-alkylo, -N (alkyl) ) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2N H2, - (CH2) m-heteroaryl, - (CH2) mS-ary lo, - (CH2) mS-heteroary lo, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroarylo, and - (CH2) mSO2NH-alkyl, wherein alkyl is defined as above, and m is 0, 1, 2 or 3. The term "arylalkyl" means an alkyl portion thereof. (as defined above) substituted with an aryl moiety (also as defined above). An arylalkyl can be substituted ("substituted arylalkyl") by 1 to 3 substituents selected from the group as defined above by "substituted aryl". By halogen, in the present invention, fluoro, bromo, chloro, and iodo is meant. By heteroaryl (aromatic heterocycle) in the present invention is meant one or more 5-, 6-, or 7-ring aromatic ring systems containing at least and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazole, (is) oxazolyl, pyridyl, pyrimidinyl, (iso) quinoline, naphthyridinyl, benzimidazolyl and benzaxazolyl. The term "substituted heterocycle" means a substituted heterocycle. by 1 to 3 substituents selected from the group as defined above for "substituted aryl". The term "heteroarylalkyl" means an alkyl portion (as defined above) substituted with a heteroaryl moiety (also as defined above). A heteroarylalkyl can be substituted ("substituted heteroarylalkyl") by 1 to 3 substituents selected from the group as defined above for "substituted aryl". The symbol "-" means a link. The following abbreviations are used in solitude. HPLC High pressure liquid chromatography mp Melting point TH F tetrahydrofuran APCl Atmospheric pressure chemical ionization EM Mass spectrometry DMF N, N'-Di methyl formamide Et3N Triethylamine FABH RMS Fast atom bombardment, high resolution mass spectrometry R1 and R2 groups can be linked to the dihydro-naphthalenone ring system directly through a linker, or through a lower alkyl group, such alkyl being optionally interrupted by a linker selected from O O O -NHC-, -CNH, -CO-, S, SO, SO2, O and NH. Examples of such groups are - (CH2) mN H-aryl, -CH2NHC-R2, - (CH2) mSO2-alkyl, - (CH2) m-SO2-phenyl, -CH2CH2-SO2iPr, O -NHC-phenyl, -NHCO-aryl-NH pyridyl, CH2O-alkyl, - (CH2) m CO2-alkyl, and CH2O-thiazolyl, where m is 0, 1, 2 or 3. The term "patient" means all the animals, preferably mammals, including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep and pigs. The term "treating" for purposes of the present invention refers to prophylaxis or prevention, improvement or elimination of a named condition once the condition has been established. A "therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient to ameliorate or treat a symptom of restenosis, cancer or atherosclerosis, or prevent restenosis or atherosclerosis. A therapeutically effective amount of a compound of the present invention can be readily determined by one skilled in the art by administering an amount of a compound to a patient and observing the result.

In addition, those skilled in the art are familiar with identification patients who have cancer, restenosis or atherosclerosis or who are in danger of having restenosis. The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, uterus, fallopian tubes, endometrium, vagina, vulva, cervix, prostate, testes, penis, esophagus, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, cutaneous or intraocular melanoma, lung, endocrine system, thyroid gland, parathyroid gland , adrenal gland, soft tissue sarcoma, squamous cell carcinoma, large cell carcinoma, adenocarcinoma, bone, colon, adenocarcinoma, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papilloma carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, carcinoma of the liver and bile passages, kidney carcinoma, urethra, renal cell carcinoma, renal pelvis carcinoma, myeloid disorders, lymphoid disorders, Hodgkins, vel slab cells, cavity and oral pharynx (oral), lip , tongue, mouth, pharynx, small intestine, colorectum, cancer of the anal region, large intestine, rectum, cancer of the head or neck, brain and central nervous system, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal vertebra tumors, brainstem glioma, pituitary adenoma, chronic or acute leukemia and lymphocytic lymphomas. The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein is refer to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are within the scope of legitimate medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation , allergic response, and the like, in proportion to a reasonable benefit / risk ratio, and effective for its intended use, as well as the zwitterionic forms, when possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or separately by reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salts thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate salts , mesylate, glucoheptonate, lactobionate and lauryl sulphonate, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium , methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference). Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include C-alkyl esters. -Cß wherein the alkyl group is a straight or branched chain. Acceptable esters include Cs-C cycloalkyl esters as well as arylalkyl esters such as, but not limited to, benzyl. Alkylesters of Ci-C4 are preferred. The esters of the compounds of the present invention can be prepared according to conventional methods. Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention include amides derived from ammonia, C-alkylamines. -Cß primary, and dialkylamines of C. -Cß secondary wherein the alkyl groups are straight or branched chain. In the case of the secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, C alkylamines are preferred. -C3 primary, and dialkylamines of C. -C2 secondary. The amides of the compounds of the invention can be prepared according to conventional methods. The term "prodrug" refers to compounds that rapidly transform in vivo to produce the compound of the above formulas, for example, by hydrolysis in the blood. A full discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delirium Systems," Vol. 14 of the A.C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The representative compounds of the invention are shown below in Table 1. 3 10 12 fifteen 17 18 19 twenty twenty-one 2. 3 24 26 27 28 Representative compounds of the present invention, which are encompassed by Formulas IX, and preferably VX Formulas, include but are not limited to the compounds in Table 1 and their pharmaceutically acceptable acid or base addition salts, or amide, or prodrugs of the same. Preferred compounds of Formula V are those wherein R 1 is hydrogen; R 2 is hydrogen, lower alkyl, arylalkyl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl or alkoxycarbonylalkyl; Cast; n is 2; Ra and R are hydrogen; R ° is hydrogen; and R3 is arylalkyl. Preferred compounds of Formula V are 4- (. {5- [2- ( { D-Oxo-1 - [(2-pyridinylsulfonyl) methyl] -5,6,7,8-tetrahydro-2- Naphthalenyl.} oxy) ethyl] -1 H -imidazol-1-yl.] methyl) -benzonitrile and 4- (. {5- [2- ( { 1 [(lsopropylsulfonyl) methyl] -5- oxo-5,6,7,8-tetrahydro-2-naphthalenyl}. oxy) ethyl] -1 H -imidazo 1-1 -yl.} methyl) benzonitrile. Preferred compounds of Formulas IX and X are those wherein R 2 is hydrogen, C alkyl. -Cβ, aryl, heteroaryl, arylalkyl, heteroarylalkyl or the arylalkyl is substituted with - (CH2) mC02H; the linker is selected from the group consisting of -NHCO, -CO2, SO2, O, and -NH and R2 is C-alkyl. -Cß, aryl or heteroaryl; and R4 is hydrogen. The compounds of the present invention can be administered to a patient alone or as part of a composition containing other components such as excipients, diluents, and carriers, such as excipients. pharmaceutically acceptable diluents and carriers, such as pharmaceutically acceptable excipients, diluents, and carriers, all of which are well known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracystorically, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as buccal or nasal sprays. Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters injectables such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants. The prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. This may also be desirable to include isotonic agents, for example sugar, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the use of absorption retardation agents, for example, aluminum monostearate and gelatin. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound is mixed with at least one usual inert carrier (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose , mannitol and silicic acid; (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, silicate of certain complexes, and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as, for example, kaolin and bentonite; e (i) lubricants, such as example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laurisulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise regulating agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like. Dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and frameworks, such as enteric coatings and others well known in the art. They may contain opacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a suspended manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils, in particular, cottonseed oil, peanut oil, corn germ oil, o oil, castor oil and sesame oil; glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances, cremophor and the like. In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfume agents. The suspensions, in addition to the active compounds, may contain suspending agents, for example, isostearyl ethoxy alcohols, polyoxyethy lensorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances, and the similar ones. Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a wax suppository, which are solids at ordinary temperatures but are free of charge. liquids in body temperature and therefore, they melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, regulators, or propellants as may be required. Ophthalmic formulations, ointments for eyes, powders and solutions are also contemplated as being within the scope of this invention. The compounds of the present invention can be administered to a patient at dose levels in the range of about 0.1 to about 2,000 mg per day. For a normal adult human having a body weight of about 70 kilograms, a dose in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferred. The specific dose used, however, may vary. For example, the dose may depend on a number of factors including the requirements of the patient, the severity of the treated condition, and the pharmacological activity of the compound used. The determination of optimal doses for a particular patient is well known to those skilled in the art. The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention. In addition, the compounds of the present invention can exist in unsolvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention. The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification of the claims in any way. An illustration of the preparation of the compounds of the present invention is shown in Schemes 1 to 3, R1, R2 and R3 are as defined above for Formula V and "Ar" represent aryl or substituted aryl. The definitions of R1, R2 and R3 correlate with the definitions of R1 ', R2' and R3 'in Formula I. Constructed with the description provided herein (particularly the schemes and the synthetic examples that follow) and common knowledge to all those who practice in the field, those of ordinary experience in the art could performed and used the full scope of the compounds described herein. The compounds of the invention can be prepared by any of the various synthetic routes using readily available starting materials and intermediates. The compounds of Formula I or V are usually prepared by coupling a 6-hydroxy-tetralone with a hydroxyalkyl-imidazole, as shown, for example, as the last step in Schemes 1 to 3. The reaction is carried out in the presence of a triarylphosphine and dialkyl azodicarboxylate. Scheme 1 shows a typical synthesis of the hydroxyalkyl imidazole, starting from readily available cyanoalkyl imidazole. The secondary nitrogen of the iodide is protected, for example, with a t-BOC group, and the desired R3 group (for example, arylalkyl such as benzyl) is then added by reacting the protected imidazole with R3-L, when L is a leaving group such as halo or hydroxy. The reaction is generally carried out in the presence of an acid such as sulfuric acid or methanesulfonic acid, which also eliminates the protecting group N. The cyano group is then hydrolyzed to a carboxylic acid by reaction with a strong base such as hydroxide. of sodium, and the acid can be esterified by reaction with an alcohol. The ester is then easily reduced by reaction with lithium aluminum hydride or similar reducing agent to give the desired hydroxyalkyl imidazole. The hydroxyalkyl imidazole is then reacted with a substituted 6-hydroxytetralon in the presence of an arylphosphine such as triphenylphosphine, and a dialkyl azodicarboxylate (e.g., a Mitsunobu esterification reaction).

Scheme 1 diethyl azodicarboxylate Scheme 2 shows another typical synthesis of an alkylimidazole derivative which can be coupled to a 6-hydroxytetralon to give compounds of the invention. In Scheme 2, a carboxyalkyl imidazole is converted to an ester by the reaction with an alcohol. The secondary amino nitrogen of the imidazole is protected with a common nitrogen protection group such as triphenylmethyl. The protected midazole is reacted with an arylalkyl halide (R3-L) to provide the desired substituted imidazole reagent, which is then coupled with the 6-hydroxy tetralon as in Scheme 1.

Scheme 2 chlorotriphenylmethane triethylamine diet azodicarphoxylate Scheme 3 illustrates another method for making substituted imidazoles that can be coupled to a 6-hydroxy-tetralone to provide compounds of the invention of the Formulas I or V. The scheme starts with 4-formylimidazole. The nitrogen t (tau) is protected with a typical nitrogen protection group such as triphenylmethyl (trityl-TRT). The formyl group is converted to a secondary alcohol by reaction with an aryl lithium reagent (J. Heteroeyelie Chemistry, 1993; 30 (6), 1645-1651). The ring nitrogen p (pi) of the imidazole is derivatized by reaction with a suitable reagent, such as an aralkyl-protected L-alkoxy, wherein L is a leaving group, such as halogen, mesylate, or tosylate; preferably, an alkoxyhalide protected with benzyl. The removal of the protection groups by standard method produces a hydroxyalkyl-imidazole, which is coupled to the 6-hydroxytetralon as described in Scheme 1. The descriptions in this application of all articles and references, including patents, are incorporated herein by reference. The invention is further illustrated by the following examples which will not be construed as limiting the invention in scope or spirit to the specific procedures described therein. The starting materials and several intermediates can be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well-known synthetic methods. Representative examples of methods for preparing the compounds of the invention, as well as intermediates of the invention are set forth below.

EXAM PLO 1 Synthesis of 6-. { 2- [3- (4-methoxy-3-methyl-benz I) -3H -i m-dazol-4-yl] -ethoxy} -3,4-dihydro-2H-naphthalen-1 -on (Compound 12) 1. 4-Cyanomethyl-1-midazole-1-carboxylic acid tert-butylester A solution of 4 (5) -cyanomethylimidazole (12.2 g, 0.1 mole) in methanol (150 ml) is cooled to 0 ° C, and then a solution of di-tert-butyl dicarbonate (30 g, 0.137 moles) is added. ) in methanol (75). The reaction is stirred under a nitrogen atmosphere and allowed to warm to room temperature overnight. The solution is concentrated in vacuo and the residue is taken up in isopropyl ether and concentrated in vacuo. The residue is taken in ether Isopropyl and cool for several hours. The crystalline product is collected by filtration. The mother liquor is purified by flash chromatography (chloroform: acetone / 9: 1) to give 5.7 grams of the title compound (27% yield). 2. [3- (4-M-ethoxy-3-methyl-benz I) -3H-imidazol-4-yl] -aceto or tri lo A solution of methanesulfonic anhydride (7.67 g, 0.044 mol) in methylene chloride is cooled to -50 ° C. A solution of 4-methoxy-3-methyl-benzyl alcohol (6.69 g, 0.044 mol), diisopropylethylamine (7.67 ml, 0.044 mol), and methylene chloride (60 ml) is added in drops. The solution is stirred at -50 ° C for 15 minutes and heated at -20 ° C for 15 minutes. The reaction vessel is again cooled to -50 ° C and a solution of the product is added dropwise from step 1, 4-cyanomethyl-imidazole-1-carboxylic acid tert-butylester (9.07 g, 0.0438 moles) , in methylene chloride (60 ml). It is added to the reaction mixture and stirred vigorously for 30 minutes a solution of 0.25 M potassium phosphate buffer (pH 7, 300 ml). The organic phase is separated, washed with phosphate buffer, dried over magnesium sulfate, and concentrated in vacuo. The product is purified by flash chromatography (0-1% methanol in chloroform) to give an oil which is dissolved in methylene chloride; the solution is evaporated and dried at 0.5 mm to give a crystallized product (4.3 g, 41% yield). 3. 3- (4-Methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -acetic acid The product obtained in step 2, [3- (4-methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -acetonitrile (4.3 g, 0.0178 moles), is suspended in 2N NaOH (18 ml) , and refluxed for 4 hours. The solution is cooled and neutralized with 1 N HCl (36 ml), diluted with ethanol (100 ml) and concentrated in vacuo. The residue is taken up in ethanol (250 ml), the precipitate is filtered and the solution is filtered and concentrated in vacuo. The residue is ground with acetate hot ethyl, cooled and filtered to give an off-white solid (4.5 g, 97% yield); mp: 1 17-121 ° C. 4. [3- (4-Methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -acetic acid ethyl ester The product obtained in step 3, [3- (4-methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -acetic acid, (3.4 g, 0.013 mol) is dissolved in ethanol ( 100 ml) and triethyl orthoformate (5 ml). This solution is saturated with dry HCl and the reaction is heated to reflux for 5 hours. The solution is concentrated in vacuo; The residue is triturated with ethyl acetate and dried overnight at 65 ° C under vacuum to give 3.95 g (93% yield of the desired product. 5. 2- [3- (4-Methoxy-3-methyl-benzy.) -3H -i midazoi-4-yl] -ethane! A suspension of the product starting from step 4, [3- (4-Methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -acetic acid ethyl ester (3.9 g, 0.012 mol), in tetrahydrofuran ( 250 ml) is stirred vigorously under a nitrogen atmosphere for 30 minutes. Then add lithium aluminum hydride (0.5 g, 0.013 mol) slowly in 5 portions. The reaction is stirred 30 minutes at 0 ° C, warmed to room temperature for 3 hours, and then brought to reflux for 1 hour. The reaction is abruptly quenched by the drip addition of water (0.9 ml) and the salts Li / AI are removed by filtration through Celite, rinsing thoroughly with tetrahydrofuran: methanol (95: 5). The filtrate is concentrated in vacuo to give the product (2.37 g, 80% yield). 6. 6-. { 2- [3- (4-Methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -ethoxy} -3,4-dihydro-2H-naphthalen-1 -one Dissolve 6-hydroxy-tetralone (0.48 g, 0.003 mole) in tetrahydrofuran (30 ml). Triphenylphosphine (1.11 g, 0.0042 mol) is added followed by the product from step 5, 2- [3- (4-methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -ethanol (0.75 g). g, 0.003 moles). A solution of diethyl azodicarboxylate (0.6 ml, 0.0038 mol) in tetrahydrofuran (10 ml) is slowly added under a nitrogen atmosphere. The reaction is stirred at room temperature overnight under a nitrogen atmosphere. The precipitate is filtered, and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is purified by flash chromatography (5% methanol in chloroform) to give 0.51 g (43% yield) material which is further purified by reverse phase HPLC (column C-18, 22 x 250 mm, 0.1 mm, 300 A gradient: 10% to 40% acetonitrile, 0.1% trifluoroacetic acid, against 1% aqueous trifluoroacetic acid, 100 minutes, 13 ml / minutes) to give 0.070 g of Compound 12 (6% yield). MS: APCl: M + 1: 391.2 (M: 390.5).

Analysis calculated for C 24 H 26 N 2 O 31.25 CF 3 COOH: C, 59.72; H, 5.15; N, 5.26 Found: C, 59.71; H, 5.13; N, 5.19.

EXAMPLE 2 Synthesis of 6- [2- (3-benzyl-3H-imidazol-4-yl) -ethoxy] -5-propyl-1,3,4-dihydro-2H-naphthalen-1-one (Compound 2) 1. Ethyl ester (1 H-imidazol-4-yl) -acetic acid The 4-imidazoleacetic acid hydrochloride (5 g, 0.03 mole) is dissolved in methanol (5 g, 0.03 mole) in methanol (100 ml) and the solution is saturated with dry HCl. The reaction is stirred overnight at room temperature under a nitrogen atmosphere. The solution is concentrated in vacuo and the residue is dried to give the product (5.13 g, 0.029 mole). 2. (1-Trityl-1H-imidazol-4-yl) -acetic acid ethyl ester The product from step 1, (1 H-imidazol-4-yl) -acetic acid ethyl ester, (5.13 g, 0.029 mole) is suspended in dimethylformamide (25 ml) and triethylamine (12.5 ml, 0.09 mole) is added immediately. by chlorotriphenylmethanol (9.88 g, 0.036 moles). The suspension is stirred overnight at room temperature under a nitrogen atmosphere. Ethyl acetate (250 ml) is added to the reaction mixture followed by water (100 ml). The organic phase is collected and washed three times with saturated sodium bicarbonate, washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (quantitative yield). 3. Ethyl ester (3-Benzyl-3H-imidazol-4-yl) -acetic acid The product of step 2, (1-trityl-1H-ylamidazol-4-yl) -acetic acid ethyl ester (12.33 g, 0.032 mole), is dissolved in acetonitrile (100 ml). Benzyl bromide (4.7 ml, 0.040 mol) is added and the reaction is refluxed overnight under a nitrogen atmosphere. The solution is cooled and concentrated in vacuo.

The residue is dissolved in ethyl acetate and the resulting precipitate is filtered. The solid is dissolved in methanol and heated to reflux for 3 hours, and then stirred overnight at room temperature under a nitrogen atmosphere. The solution is concentrated and ethyl acetate is added to the residue. The precipitate obtained is filtered, washed with ethyl acetate, and dried. The solid is then suspended in 1: 1 saturated sodium bicarbonate; methylene chloride and stirred for 2 hours. The organic phase is collected, dried over magnesium sulfate, filtered, concentrated and dried to give the product (3.80 g, 52% yield). 4. Acid (3-Benzyl-3H-i midazole-4-l) -acetic The product from step 3, (3-benzyl-3H-imidazol-4-yl) -acetic acid ethyl ester (3.80 g, 0.016 mol), is dissolved in methanol (50 ml) and tetrahydrofuran (50 ml) is then added. and 1 N NaOH (48 ml). The reaction is stirred overnight at room temperature. 2N HCl (24 ml) is then added and the Solution is concentrated in vacuum. The residue is suspended in water and lyophilized to give the product (6.28 g, quantitative yield). 5. 2- (3-Benzyl-3H-imidazol-4-yl) -ethanol The product from step 4, (3-benzyl-3H-imidazol-4-yl) -acetic acid (6.28 g, 0.016 mol), is dissolved in tetrahydrofuran (50 ml). Lithium aluminum hydride (98%, 1.48 g, 0.038 mol) in tetrahydrofuran (50 ml) is suspended and the solution is added dropwise to the acid solution at room temperature under a nitrogen atmosphere. Once the addition is complete, the reaction is stirred for 1 hour at room temperature, 4 hours at reflux, and overnight at room temperature, all under a nitrogen atmosphere. The reaction is quenched by the addition of 1 N sulfuric acid (1 ml) and diluted with ethyl acetate. The gray precipitate is filtered. The aqueous phase from the filtrate is concentrated and the residue is dissolved in a minimum amount of water (100 ml). The pH is brought to 9 with the addition of 50% aqueous NaOH. The product is extracted with methylene chloride (5 times).

The combined organic phases are washed twice with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (1.70 g, 52% yield). 6. 6-I2- (3-Benzyl-3H-imidazol-4-yl) -ethoxy] -5-propyl I -3,4-dihydro-2H-naphthalene-1 -one 6-Hydroxy-5-propyl-3,4-dihydro-2H-naphthalen-1 -one, prepared as described in Bioorganic & Medicinal Chemistry Letters, 1994; Vol. 4 (24): 2883-2888, (0.43 g, 0.0021 mol) is dissolved in tetrahydrofuran (60 ml). Triphenylphosphine (0.86 g, 0.003 mole) is then added, followed by the product of step 5, 2- (3-benzyl-3H-imidazol-4-yl) -ethanol (0.51 g, 0.0025 mole). A solution of diethyl azodicarboxylate (0.5 ml, 0.0032 mol) in tetrahydrofuran (30 ml) is slowly added under a nitrogen atmosphere. The reaction is stirred at room temperature for 3 days under a nitrogen atmosphere. The Solution is concentrated in vacuum. The residue is taken up in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is purified by flash chromatography (0% -5% methanol in chloroform) and further purified by reverse phase HPLC (column C-18, 22 x 250 mm, 0.1 mm, 300 A, gradient, 10% -60 % acetonitrile (0.1% trifluoroacetic acid) against 1% aqueous trifluoroacetic acid, 100 minutes, 13 ml / minutes), to give 0.26 g of Compound 2 (32% yield). MS: APCl: M + 1: 389.3 (M: 388.5). Analysis calculated for C 24 H 26 N 2 O 3: 1.88 CF 3 COOH: C, 57.30; H, 5.00; N, 4.65 Found: C, 57.36; H, 4.93; N, 5.63.

EXAM PLO 3 Synthesis of 6- [2- (3-benzyl-3H-imidazol-4-yl) -ethoxy] -5-phenetii 3,4-dihydro-2H-naphthalen-1 -one (Compound 3) 1. 6-M-ethoxy-5-f-enynyl-3,4-dihydro-2H-naph talen-1 -one 5-Bromo-6-methoxy-a-tetralone, prepared as described in US Pat. No. 4,618,683, Example 89, (20.41 g, 0.08 mole) is added to a mixture of dimethylformamide (160 ml) and triethylamine (80 ml) which has It has been purged with nitrogen gas to eliminate the dissolved oxygen. This is continued by the addition of phenylacetylene (16.34 g, 0.16 mol), copper iodide (1) (0.5 g, 0.0026 mol) and dichlorobis (triphenylphosphine) palladium (11) (Aldrich Chemical Company, 2.24 g, 0.0026 mol). After stirring at 25 ° C for 20 minutes, the mixture is heated at 108 ° C for 2 hours. At the same time, an additional amount of phenylacetylene is added (31 g, 0.303 mole) in droplets for 2 hours, followed by heating at 108 ° C for 16 hours. The mixture is then evaporated in vacuo to remove the solvent and excess reagent obtaining a syrup. The syrup is triturated with three fractions of hot ethyl ether (750 ml), which is combined and evaporated at 5 ° C giving a suspended solid. The suspension is filtered and the solid is dried under vacuum giving 7.8 g of the product. The additional fractions are recovered by triturating hexane from the insoluble ether residues, yielding a total product yield of 10.3 g, 46.7%. This material is further purified by chromatography on 250 g of silica gel eluting with a mixture of ethyl acetate / hexane (1: 7). The appropriate fractions are evaporated to give a solid, m.p. 99 ° C to 100 ° C, 7.5 g, 33.9% yield. 2. 6-Methoxy-5-phenethyl-3,4-dihydro-2H-naphthalene-1 -one The product of step 1, 6-methoxy-5-phenylethynyl-3,4-dihydro-2H-naphthalen-1 -one (5.5 g, 0.0199 mol) is dissolved in tetrahydrofuran (250 ml) to which is added the Pd / BaSO-4 at 5% Alfa # 21 162 not reduced, (1 .4 g). The mixture is pressurized at 50 psi with H2 gas and stirred at 25 ° C for 1 hour. The mixture is filtered and evaporated to a solid, 5.7 g, 100% yield, mp 102 ° C at 1 05 ° C. The structure is verified by NMR spectrum. MS: APCl: M + 1: 281.2 (M: 280.4). 3. 6-H idroxy-5-phenethyl-3, 4-dihydro-2H-naphthalene-1 -one The product of step 2, 6-methoxy-5-phenethyl-3,4-dihydro-2H-naftaien-1 -one (5.5 g, 0.0196 g) is dissolved in dimetiisulfóxido (30 ml) and added sodium cyanide finally ground (4.8 g, 0.096 moles). The mixture is then placed alternately under vacuum and nitrogen atmosphere to remove dissolved oxygen and leave under nitrogen atmosphere. The mixture is heated at 180 ° C for 5 hours, followed by cooling to 100 ° C. The solution is poured into 200 ml of cold water rapidly stirred and acidified by the addition of concentrated HCl to pH 1. The solution is filtered and extracted three times with 200 ml of ethyl ester. The ether extracts are dried over anhydrous magnesium sulfate, filtered, and evaporated to give a crystalline solid. The solid is filtered, washed with ethyl ether. The ether extracts are dried over anhydrous magnesium sulfate, filtered, and evaporated to give a crystalline solid. The solid is filtered, washed with ethyl ether, and dried at 60 ° C in vacuo to give a yellow-green solid, 3.9 g, 75% yield. The structure is verified by NMR spectrum. MS: APCl: M + 1: 267.1 (M: 266.34). 4. 6- [2- (3-Benzyl-3H-imidazol-4-yl) -ethoxy] -5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 3) The product of step 3, 6-hydroxy-5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (1.31 g, 0.005 mole), is dissolved in tetrahydrofuran (100 ml). Triphenylphosphine (2.0 g, 0.0076 mol) is then added followed by the product from step 5, Example 2, 2- (3-benzyl-3H-imidazol-4-yl) -ethanol (1.19 g, 0.0059 mol). A solution of diethyl azodicarboxylate (1.18 ml, 0.0075 mole) in tetrahydrofuran (30 ml) under a vacuum is slowly added. nitrogen atmosphere. The reaction is stirred at room temperature for 5 days under a nitrogen atmosphere. The solution is concentrated in vacuo. The residue is taken up in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product is purified by flash chromatography (0% -5% methanol in chloroform) and further purified by reverse phase HPLC (column C-18; 22 x 250 mm; 0.1 mm; 300 A; gradient: 10% -50 % acetonitrile (0.1% trifluoroacetic acid) against 1% trifluoroacetic acid, 100 minutes, 13 ml / minute), to give 0.05 g of Compound 3 (2.2% yield). MS: APCl: M + 1: 451.2 (M: 450.6). Analysis calculated for C30H30N2O21.06 CF3COOH 0.75 H2O C, 65.95; H, 5.61; N, 4.79. Found: C, 65.99; H, 5.33; N, 4.61.

EXAMPLE 4 Synthesis of 4- ( { 5- [2- ( { 5-oxo-1 - [(1-pyridin-ylsulfonyl) methyl] -5,6,7,8-tetrahydro-2-naphthalenyl} oxy) ethyl] -1 W-imidazo-1-yl.} methyl) benzonitrile (Compound 28) 1. 4-. { [5- (2-hydroxyethyl) -1 W-imidazol-1-yl] methyl} benzonitrile A mixture of 1- (triflumethyl) -4- (2-hydroxyethyl) imidazole (13 g, 36.7 mmol) [C.R. Ganellin et al., J. Med. Chem., 1996, 39, 3806] and 4- (bromo-methyl) benzonitrile (8.6 g, 44 mmol) in 100 ml of acetonitrile was heated under reflux for 2 days, and the solvent It was removed under vacuum. The residue was then triturated twice with ethyl acetate, and the organic layer was discharged. The resulting residue was then dissolved in 100 ml of methanol and heated under reflux for 24 hours. The methanol was then stirred under vacuum and the product was dissolved in 100 ml of 2M HCl. After being filtered to remove triphenylmethanol, the solution was basified with NH4OH4, and the product was extracted with CH2CI2 to give 2.24 g of an oil crude which was triturated with ethyl acetate to give a white solid, 1.05 g, 12.6 % yield, mp 115-116 ° C. The NMR spectrum was consistent with the structure. MS: APCI: M + 1: 228.0 (M: 227.1). 2. 6-H idroxy-5- (pyridine-2-ylsulfanyl methyl) -3, -dihydro-2H-naphthal en-1-one Tetrahydrofuran (500 ml) is added to 2-mercaptopyridine (16 g, 0.14 mol) and triethylamine (20.8 ml, 0.15 mol). The mixture was heated to 30 ° C, followed by the addition of a solution of 5-chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one, prepared as described in Chem. Pharm. Bull. 25 (11) 2988-3002 (1977), (29.5 g, 0.143 mol) in tetrahydrofuran 300 ml) giving a suspension. The mixture was stirred for 18 hours at 25 ° C. The suspension was filtered, and the filtrate was evaporated under vacuum to give a solid. The solid was dissolved in hot ethyl acetate, washed with 300 ml of water, brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to a small volume, giving a suspended solid. The solid was filtered, washed with ethyl acetate, and dried under vacuum to a solid, 22.26 g, 56% yield. NMR spectrum was consistent with the structure. MS: APCl: M + 1: 286.1 (M: 285.4). 3. 6-Hydroxy-5- (pyridin-2-sulfonylmethyl) -3,4-dihydro-2H-naphthalene-1 -one The product from step 2, 6-hydroxy-5- (pip "din-2-ylsulfanylmethyl) -3,4-dihydro-2H-naphthalene-1 -one (18 g, 0.063 moles), is added to dichloromethane (400 ml) A solution of m-chloroperbenzoic acid (70%, 33.6 g, 0.136 mol) in dichloromethane (250 ml) was added over 2 hours, after which the mixture is allowed to stir for 18 hours at 25 ° C. The mixture was filtered, and the solid was resuspended in hot ethyl acetate and extracted with saturated sodium bicarbonate solution.The organic phase was washed with brine, dried over anhydrous magnesium sulfate and filtered. giving a solid, which was filtered, washed with ethyl acetate and dried, 6.8 g, 34% yield The NMR spectrum was consistent with the structure MS: APCl: M + 1: 318.3 (M: 317.4) . 4. 4- ( { 5- [2- ( { 5-oxo-1 - [(2-pyridinylsulfonyl) met!] -5.6,7,8-tetrah id ro -2 -naf tal eni l .}. -oxi) eti I] -1-imidazol-1-yl.] methyl) benzonitrile A mixture of the product of step 1, 4-. { [5- (2-hydroxyethyl) -1 H -imidazol-1-yl] methyl} benzonitrile (0.26 g, 1.1 millimoles), the product of 3,6-hydroxy-5- (pyridin-2-sulfonylmethyl) -3,4-dihydro-2H-naphthalen-1 -one (0.32 g, 1 mmoles) and triphenylphosphine (0.42 g, 1.6 millimoles) in 5 ml of dry tetrahydrofuran was cooled to 0 ° C and treated dropwise with diisopropyl azodicarboxylate (0.3 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 days and the solvent was removed. The residue was extracted into dichloromethane, washed with water, and dried over Na 2 SO 4. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with 5% methanol in dichloromethane, to give 0.28 g ( 53% yield) of the unpurified product, a sample of which was further purified by high pressure liquid chromatography [Bondclone-10 column 18 eluting with a 58% (9: 1) acetonitrile-water mixture and 42% 0.045 MN H4HC02 (pH 3.49)] to give Compound 28 as a white solid (99% pure by HPLC). FABH RMS 527.1771 3 (MH + 517.17530).

EXAMPLE 5 Synthesis of 4- ( { 5- [2- ( { 1 - [(isopropylsulfortyl) methyl] -5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl} oxy. ) eti!] - 1 H-imidazol-1-yl.} - methyl) benzonitrile (Compound 29) 1.6 -H i droxi-5-i sopropil sulf ani I methyl -3,4-dihyd ro-2H -naf talen-1-one Tetrahydrofuran (100 ml, anhydrous, distilled) is sprayed with nitrogen gas followed by the addition of triethylamine (6.97 ml, 50 mmol) and 2-propantiol (7 ml, 150 mmol). A solution of 5-chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one, prepared as described in Chem. Pharm. Bull. 25 (11) 2988-3002 (1977), (10.53 g, 50 mmol) in tetrahydrofuran (175 ml). The mixture was stirred for 1 hour at 25 ° C, followed by heating at 85 ° C for 3 hours. The mixture was filtered, and the filtrate was evaporated under vacuum to give a solid. The solid was dissolved in ethyl acetate, washed with 1N citric acid and brine. The organic phase was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a solid which was filtered, washed with ethyl ether, and dried in vacuo to a sol, 8.69 g, 69.4% yield. The N MR spectrum was consistent with the structure. MS: APCl: M + 1: 251.2 (M: 250.4). 2. 6-H id roxi -5-ssopropiisulf oni! methyl -3,4-dihyd ro-2H -naf talen-l ona The product of step 1, 6-hydroxy-5-isopropylsulfanylmethyl-3,4-dihydro-2H-naphthalen-1 -one (3.74 g, 14.9 mmol) was added to dichloromethane (100 ml). The mixture was cooled to 15 ° C, followed by the addition of m-chloroperbenzoic acid (70% with water, 7.36 g, 29.9 mmol) for 2 minutes. The mixture was stirred for 5 hours at 25 ° C to give a suspended solid. The suspension was evaporated under vacuum to give a solid. The solid was dissolved in hot ethyl acetate (700 ml), washed with saturated sodium bicarbonate and brine. The organic phase was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to 150 ml in volume at 2 ° C, giving a suspended solid. The solid was filtered, washed with ethyl ether, and dried vacuum to a solid, 2.64 g, 63% yield. The NMR spectrum was consistent with the structure. MS: APCl: M + 1: 283.0 (M: 282.36). 3. A mixture of the product of Example 4, step 1, 4-. { [5- (2-hydroxyethyl) -1 H -imidazol-1-yl] methyl} benzonitrile (0.26 g, 1.1 mmol), the product of 2,6-hydroxy-5-isopropylsulfonylmethyl-3,4-dihydro-2H-naphthalene-1 -one (0.28 g, 1 mmol) and triphenylphosphine (0.42 g, 1.6 mmoles) in 5 ml of dry tetrahydrofuran was cooled to 0 ° C and treated dropwise with diisopropyl azodicarboxylate (0.3 g, 1.5 mmoles). The resulting mixture was stirred at room temperature for 2 days and the solvent was removed. The residue was extracted into dichloromethane, washed with water, and dried over Na 2 S 4. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with 5% methanol in dichloromethane, to give an unpurified product which was further purified by high pressure liquid chromatography [Bondclone-10 Column 18 eluting with a mixture of 58% acetonitrile-water (9: 1) and 42% 0.045 M of N H4HC02 (pH 3.49)] to give Compound 29 as a white solid, 0.06 g (12% yield, 95% pure by HPLC). FABH RMS 492.19678 (MH + 492.19570).

EXAMPLE 6 Synthesis of 4-. { [5- (2- { [5-oxo-1- (2-phenylethyl) -5,6,7,8-tetrahydro-2-naphthalenyl] oxy} ethyl) -1 / -imidazole-1 - il] metii} benzonitrile (Compound 4) 1. A mixture of the product of Example 4, step 1, 4-. { [5- (2-hydroxyethyl) -1 H -imidazol-1-yl] methyl} benzonitrile (1.3 g, 5 mmol), the product of Example 3, step 3, 6-hydroxy-5- (2-phenylethyl) -3,4-dihydro-1 (2 / - /) - naphthalenone (1. 14 g, 5 mmol) and triphenylphosphine (1.97 g, 7.5 mmol) in 25 ml of dry tetrahydrofuran was cooled to 0 ° C and treated dropwise with diisopropyl azodicarboxylate (1.30 g, 7.5 mmol). The resulting mixture was stirred at room temperature for 5 days and the solvent was removed. The residue was extracted into dichloromethane, washed with water, and dried over Na 2 SO 4. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with ethyl acetate-methanol 3: 1, give an unpurified product which was further purified by chromatography on alumina, eluting with 99: 1 dichloromethane-methanol to give a white solid, 1.29 g (54% yield) Recrystallization from dichloromethane-isopropanol gave the melting material at 179.180 ° C. Analysis calculated for C3? H2gN3O2: Theory: C, 78.29; H, 6.15; N, 8.84 Found: C, 78.12; H, 6.28; N, 8.89.

EXAMPLE 7 The following compounds are prepared essentially according to the procedures described in Examples 1 to 6 and are shown in Schemes 1 to 3: (a) 4-. { 5- [2- (5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] imidazol-1-ylmethyl} benzonitrile (Compound 1); (b) 4- (2-. {2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydronaphthalene-1-yl acid .) ethyl) benzoic acid (Compound 5); (c) 6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -5-phenylaminomethyl-3,4-dihydro-2H-naphthalene-1 -one (Compound 6); (d) 5-benzyl-6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -3,4-dihydro-2H-naphthalene-1 -one (Compound 7); (e) 6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -5-phenylamino-3,4-dihydro-2H-naphthalen-1 -one (Compound 8); (f) N-. { 2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalene-1-yl} benzamide (Compound 9); (g) 6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -5-isopropoxymethyl-3,4-dihydro-2H-naphthalen-1 -one (Compound 10); (h) 3- methyl ester. { 2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl} propionic (Compound 11); (i) 6- [2- (3-benzyl-3H-imidazol-4-yl) -1-phenylethoxy] -3,4-dihydro-2H-naphthalen-1-one (Compound 13); (j) 4-. { 3- [2- (5-oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] -3H-imidazol-4-yl} methyl) benzonitrile (Compound 14); (k) 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-propyl-3,4-dihydro-2H-naphthalen-1-one (Compound 15); (I) 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 16); (m) 4-. { 3- [2- (5-oxo-1-phenethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] -3H-imidazol-4-yl} methyl) benzonitrile (Compound 17); (n) 4- (2-. {2- [2- (5-Benzyl-imidazol-1-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl} acid} ethyl) benzoic (Compound 18); (o) 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-phenylaminomethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 19); (p) 5-benzyl-6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -3,4-dihydro-2H-naphthalen-1-one (Compound 20); (q) 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-phenylamino-3,4-dihydro-2H-naphthalen-1-one (Compound 21); (r) N- [2- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl} benzamide (Compound 22); (s) 6-. { 2- [3- (methoxy-3-methylbenzyl) -3H-imidazol-4-yl] ethoxy} -5-phenethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 23); (t) 6- [2- (5-Benzyl-3H-imidazol-1-yl) -ethoxy] -5- (2-pyridin-2-yl-ethyl) -3,4-d-hydroxy-2H -naphthalene-1 -one (Compound 24); (u) 6-. { 2- [3- (4-Methoxy-3-methyl-l-benzyl) -3H-α-midazol-4-yl] -ethoxy} -5- (2-pyridin-2-ylethyl) -3,4-dihydro-2H-naphthalen-1 -one (Compound 25); (v) 5-Benzylsulfonylmethyl-6-. { 2- [5- (4-methoxy-3-methybenzyl) imidazol-1-yl] ethoxy} -3,4-dihydro-2H-naphthalen-1 -one (Compound 26); and (w) 5- Benzene sulfonylmethyl-6-. { 2- [3- (4-methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] ethoxy} -3,4-dihydro-2H-naphthalen-1 -one (Compound 27).

EXAMPLE 8 The pharmaceutical utility of the compounds of this invention was stabilized by the following standard analysis which measures the inhibition of the enzyme protein: farnesi I transferase (PFT), also mentioned as a protein of farnesyl transferase (FPT). Inhibitory Activity of PFT The PFT (or FPT) inhibitory activity of the compounds of the present invention were analyzed in regulator H E PES (pH 7.4) containing 5 mM potassium phosphate and 20 μM ZnCI2. The solution also contained 5 mM DTT (diethiothreitol), 5 mM MgCl2, and 0.1% PEG 8000. Analyzes were performed in 96-well plates (Wallec) and solutions were employed. composed of concentrations of variation of a compound of the present invention in 10% DMSO (dimethylsulfoxide). Until the addition of both substrates, radiolabeled farnesil pyrophosphate ([13H], specific activity 15-30 Ci / moles, final concentration 134 nM) and (biotinylated) -Ahe-Thr-Lys-Cys-Val-lle-Met acid ([3aS [3a alpha, 4 beta, 6a alpha] -hexahydro-2-oxo-1 H-thieno [3,4-d] imidazole-5-pentanoic, Thr is threonine, Lys is lysine, Cys is cysteine, Val is valine, lie is isoleucine, and Met is methionine) (final concentration 0.2 μM), the enzyme reaction was initiated by the addition of SF9 affinity purified rat FPT. After incubation at 30 ° C for 30 minutes, the reaction was terminated by diluting the mixture 2.5 times with a detection buffer containing 1.5 M magnesium acetate, 0.2 M H-3PO4, 0.5% BSA (albumen bovine serum), and strepavidin beads (Amersham) in a concentration of 1.3 mg / ml. After allowing the plate to settle for 30 minutes at room temperature, the radioactivity was quantified in a microBeta counter (Model 1450, Wallec). The analysis was also carried out without 5 mM potassium phosphate. The IC50 values (the micromolar amount of the compound of the invention required to inhibit the enzyme activity by 50%) of the compounds of Formula I or V ranges from about 0.01 to about 50.0. The inhibitory activity of the specific representative compounds are shown in Table 2.

The enzyme inhibitory activity of the compounds of the invention, as set forth in the above analysis, demonstrate that the compounds are useful in preventing and treating uncontrolled cell proliferation, and are thus useful for preventing and treating disease states characterized by such proliferation. . The compounds of Formula I or V will be used in the form of pharmaceutical formulations, and the following examples illustrate the typical dosage forms.

EXEM PLO 9 Tablet Formulation Ingredient Amount Compound No. 12 50 mg Lactose 80 mg Corn starch (for mixing) 10 mg Corn starch (for pasta) 8 mg Magnesium stearate (1%) 2 mg 150 mg Compound No. 12 is mixed with lactose and corn starch (for mixing) and combined with uniformity to a powder. The corn starch (for pasta) is suspended in 6 ml of water and heated with agitation to form a paste. The paste is added to the mixed powder, and the mixture is granulated. The wet granules are passed through a hard sieve No. 8 and dried at 50 ° C. The mixture is lubricated with 1% magnesium stearate and compressed into a tablet. The tablets are administered to a patient in a ratio of 1 to 4 each day for the prevention and treatment of atherosclerosis and cancer.

EXAMPLE 10 Parenteral Solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of Compound No. 8 are added.

The mixture is stirred and the pH is adjusted to 5.5 with hydrochloric acid. The volume is adjusted to 1000 ml with water for injection. The solution is sterilized, filled into 5.0 ml of ampules, each containing 2.0 ml (40 mg of Compound No. 8) and sealed under nitrogen. The solution is administered by injection to a patient suffering from cancer and who needs treatment.

EXAMPLE 11 Patch Formulation Compound No. 26 (10 mg) is suspended in a mixture of mineral oil, polyisobutylene, and colloidal silicon dioxide (5 mg each). This mixture is also applied to a microporous polypropylene membrane 10 cm2 (which has a backing layer of pigmented polyester film) which controls the ratio of the supply of the active agent to the skin surface of a patient. The membrane is covered in a polyisobutylene adhesive formulation, and the mixture is laminated with a protective liner release coating of the polyester that is removed immediately prior to applying the patch to the chest or forearm of a patient to be treated e.g. of Alzheimer's or cancer. The invention and the manner and process of carrying it out and using it, are now described in such complete, clear, concise and accurate terms as to enable any person skilled in the art to which it belongs, to make and use it. HE It will be understood that the foregoing describes preferred modalities of the present invention and that the modifications may be made herein without departing from the spirit or scope of the present invention set forth in the claims. To particularly emphasize and claim differently the subject matter with respect to the invention, the following claims conclude this specification.

Claims (1)

1. CLAIMS 1. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, characterized in that: Ra, Rb and Rc are independently hydrogen, C-Cß alkyl, C 2 -C β alkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3 , NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH alkyl, -N (alkyl) 2, - ( CH2) mP03H2, - (CH2) mP03 (alkyl) 2, - (CH2) mS02NH2, and - (CH2) mSO2NH- alkyl, wherein m is 0, 1, 2 or 3; R1 and R2 are independently hydrogen, Ci-Cß alkyl, C 2 -C β alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three independently selected groups of the group that consists of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyi, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - ( CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3, and wherein each of the groups R1 and R2 can be joined through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of OOO -NHC-, -CNH, -CO-, S, SO, S02, O and NRC; And it is NR °, O, -CHRC, or S; n is 0, 2 or 3, with the proviso that when the imidazole is bound to the imidazole nitrogen a (CRaRb) p and Y is O, NRC or S, then n is not 0; and R3 is aryl, heteroarylalkyl, or arylalkyl, wherein the aryl, heteroaryl or arylalkyl is optionally substituted with up to three groups selected from the group consisting of halogen, C-C, alkyl, amino, Ci-C, alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of d-C6, (CH2) mCO2H, (CH2) mCO2alkyl of d-C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [d-C6 alkyl] 2 > (CH2) mSO2NH2, and (CH2) mS02NHalkyl of C? -C6, where m is 0, 1, 2 or 3. 2. A compound of the formula and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R 1 and R 2 are independently hydrogen, C 1 -C 2 alkyl, C 2 -C 2 alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2 , NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2 ) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m -heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of O O O -NHC-, -CNH, -CO-, S, SO, S02, O and NRC; R ° is hydrogen, (Ci-Cß) alkyl, or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of C? -C6, (CH2) mSO3H, - (CH2 ) mPO3H2, (CH2) mPO3 [(d-C6 alkyl) 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of d-C6, where m is 0, 1, 2 or 3; and R3 is aryl, heteroarylalkyl or arylalkyl, wherein the aryl, heteroaryl or arylalkyl is optionally substituted with up to three groups selected from the group consisting of halogen, C.sub.-C.sub.be alkyl, amino, C.sub.C.sub.bexy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of d-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of d-C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C-C6 alkyl] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C.-C6, where m is 0, 1, 2 or 3. 3. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R1 and R2 are independently hydrogen, Ci-Cß alkyl, C 2 -C β alkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl , arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alky, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, N02, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m-heteoaryl, - (CH) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2, or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of O O O -NHC-, -CNH, -CO-, S, SO, SO2, O and NRC; Rc is hydrogen, Ci-Cß alkyl, or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, C 1 -Cß alkyl, amino, Ci-Cß alkoxy, hydroxy, trifluoromethyl, mono or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-Cß, (CH2) mCO2H, (CH2) mCO2alkyl of C? -C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C.sub.Cß alkyl, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C.-C6, where m is 0, 1, 2 or 3; and R5 is aryl optionally substituted with up to three groups selected from the group consisting of halogen, C.sub.-C.sub.β alkyl, amino, C.sub.1 -C.sub.2 alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy C.-C.sub.β, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of d-C6, (CH2) mC02H, (CH2) mC02alkyl of Ci-Cß, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C-alkyl] -C6] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of C? -C6, wherein m is 0, 1, 2 or 3; 4. A compound of the formula and pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein: R 1 and R 2 are independently hydrogen, C 1 -C 2 alkyl, C 2 -C 2 alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2 , NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2 ) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m -heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and - (CH2) mSO2NH-alkyl, wherein m is 0, 1, 2 or 3; and wherein each of the groups R1 and R2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such a linker selected from the group consisting of O o o -NHC-, -CNH, -CO-, S, SO, S02, O and NRC; R ° is hydrogen, Ci-Cß alkyl, or aryl; q is 1 or 2; R 4 is hydrogen, heteroaryl, or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, Ci-Cβ alkyl, amino, d-Cβ alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, Ci-Cβ thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-Cß, (CH2) mC02H, (CH2) mCO2 (C.-C6) -alkyl, (CH2) mS03H , - (CH2) mP03H2, (CH2) mP03 [C.sub.Cß alkyl, (CH2) mS02NH2, and (CH2) mS02NHalkyl of C? -C6, wherein m is 0, 1, 2 or 3; and R 5 is aryl optionally substituted with up to three groups selected from the group consisting of halogen, d-Cß alkyl, amino, Ci-Cβ alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, thioalkoxy of C.-Cß, cyano, nitro, 1,3-dioxolanyl, NHCOalkyl of C.-C6, (CH2) mC02H, (CH2) mCO2alkyl of C? -C6, (CH2) mSO3H, - (CH2) mPO3H2, (CH2) mPO3 [C? -Cß] 2, (CH2) mSO2NH2, and (CH2) mSO2NHalkyl of d-C6, wherein m is 0.1, 263. 5. The compound according to claim 1, characterized in that R1 is hydrogen. 6. The compound according to claim 1, characterized in that R 2 is hydrogen, lower alkylaryl, arylaminoalkyl, arylamino, arylcarbonylamino, alkoxyalkyl or alkoxycarbonylalkyl. 7. The compound according to claim 1, characterized in that Y is O. 8. The compound according to claim 1, characterized in that n is 2. 9. The compound according to claim 1, characterized in that Ra and Rb are hydrogen. The compound according to claim 1, characterized in that Rc is hydrogen. eleven . The compound according to claim 1, characterized in that R3 is arylalkyl. 12. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R2 is hydrogen, Ci-Cß alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with a group independently selected from the group consisting of alkyl, O-alkyl, S -alkyl OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mPO3H2, - (CH2) mPO3 (alkyl) 2, - (CH2) mSO2NH2, - (CH2) m -heteroaryl, - (CH2) ) mS-aryl, - (CH2) mS-heteroaryl, (CH2) mSO2-aryl, - (CH2) mSO2-heteroaryl, and (CH2) mSO2NH-alkyl, where m is 0, 1, 2 or 3, and in where each of the groups R 1 and R 2 can be linked through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of 0 0 0 -NHC- CNH, -CO-, S, SO, SO2, O and NH; R is hydrogen or phenyl; and R5 is aryl optionally substituted by C.sub.1C.alkyl, C.sub.C.sub.2 alkoxy, or cyano. 13. A compound of the formula X and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, characterized in that: R 2 is hydrogen, C 1 -C 7 alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with a group independently selected from the group consisting of alkyl, O-alkyl, S-alkyl OH, SH, -CN, halogen, 1,3-dioxolanyl, CF3, N02, NH2, NHCH3, N (CH3) 2, NHCO-alkyl, - (CH2) mCO2H, - (CH2) mCO2-alkyl, - (CH2) mSO3H, -NH-alkyl, -N (alkyl) 2, - (CH2) mP03H2, - (CH2) mP03 (alkyl) 2, - ( CH2) mS02NH2, - (CH2) m-heteroaryl, - (CH2) mS-aryl, - (CH2) mS-heteroaryl, - (CH2) mS? 2-aryl, - (CH2) mS02-heteroaryl, and (CH2) mS02NH-alkyl, wherein m is 0, 1, 2 or 3, and wherein each of the groups R1 and R2 can binding through a linker, or through a lower alkyl optionally interrupted by a linker, such linker selected from the group consisting of OOO -NHC-, -CNH, -CO-, S, SO, SO2, O and NH; R 4 is hydrogen or phenyl; and R5 is aryl optionally substituted by alkyl of (Ci Ce), alkoxy of (C.-Cß), or cyano. 14. The compound according to claim 12 or 13, characterized in that R 2 is hydrogen, d-Cβ alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl. 15. The compound according to claim 14, characterized in that the arylalkyl is substituted with - (CH2) mCO2H. 16. The compound in accordance with the claim 12 or 13, characterized in that the linker is selected from the group consisting of -NHCO, -CO2, SO2, O and -NH. 17. The compound in accordance with the claim 16, characterized in that R2 is (Ci-C) alkyl, aryl, or heteroaryl. 18. The compound in accordance with the claim 13 or 13, characterized in that R4 is hydrogen. 1 9. The compound in accordance with the claim 1, characterized in that it is selected from the group consisting of 4-. { 5- [2- (5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] imidazol-1-ylmethyl} benzonitrile; 4-. { 5- [2- (5-Oxo-1-phenethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] imidazol-1-ylmethyl] benzonitrile; 4- (2- { 2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl} acid. ethyl) benzoic; 6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -5-phenylaminomethyl-3,4-dihydro-2H-naphthalene-1 -one; 5-benzyl-6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -3,4-dihydro-2H-naphthalen-1 -one; 6- [2- (3-benzyl-3H-imidazoI-4-yl) ethoxy] -5-phenylamino-3,4-dihydro-2H-naphthalen-1 -one; N-. { 2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl} benzamide; 6- [2- (3-benzyl-3H-imidazol-4-yl) ethoxy] -5-isopropoxymethyl-3,4-dihydro-2H-naphthalen-1 -one; 3-methyl ester. { 2- [2- (3-Benzyl-3H-imidazol-4-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalene-1-yl} propionic; 6- [2- (3-benzyl-3H-imidazol-4-yl) -1-phenylethoxy] -3,4-dihydro-2 H -naphtha I en-1 -one; 4-. { 3- [2- (5-oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] -3H-imidazol-4-yl} methyl) benzonitrile 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-propyl-3,4-dihydro-2H-naphthalen-1 -ona 6- [2- (5-benzyl-imidazole -1 -yl) ethoxy] -5-phenethyl-3,4-dihydro-2H-naphthalene-1 -one; 4-. { 3- [2- (5-oxo-1-phenethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl] -3H-imidazol-4-yl} methyl) benzonitrile 4- (2- { 2- [2- (5-Benzyl-imidazol-1-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl} ethyl) benzoic 6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -5-phenylaminomethyl-3,4-dihydro-2H-naphthalene-1 -one 5-Benzyl-6- [2- (5-benzyl-imidazol-1-yl) ethoxy] -3,4-dihydro-2H-naphthalen-1 -one 6- [2- (5-benzyl-imidazole-1 - il) ethoxy] -5-phenylamino-3,4-dihydro-2H-naphthalen-1 -one; N-. { 2- [2- (5-Benzyl-imidazol-1-yl) ethoxy] -5-oxo-5,6,7,8-tetrahydro-naphthalene-1-yl} benzamide; 6- { 2- [3- (methoxy-3-methylbenzyl) -3H-ym-dazol-4-yl] ethoxy} -5-phenethyl-3,4-dihydro-2H-naphthalen-1 -one; 6- { 2- [3- (4-methoxy-3-methyl-benzyl) -3H-imidazol-4-yl] -ethoxy} -3,4-dihydro-2H-naphthalen-1 -one; 6- [2- (3-Benzyl-3H-imidazol-4-yl) -ethoxy] -5-propyl-3,4-dihydro-2H-naphthalen-1 -one; 6- [2- (3-Benzyl-3H-imidazol-4-yl) -ethoxy] -5-phenethyl-3,4-dihydro-2H-naphthalen-1 -one 6- [2- (5-Benzyl-3H -imidazol-1-yl) -ethoxy] -5- (2-pyridin-2-yl-ethyl) -3,4-dihydro-2H-naphthalen-1 -one; 6- { 2- [3- (4-Methoxy-3-methylbenzyl) -3H-imidazol-4-yl] ethoxy} -5- (2-pyridin-2-yethyl) -3,4-dihydro-2H-naphthalen-1 -one; 5-Benzylsulfonylmethyl-6-. { 2- [5- (4-methoxy-3-methyl-benzyl) imidazol-1-yl] ethoxy) 3,4-d-hydro-2H-naphthalene-1-one; 5-Benzenesulfonylmethyl-6-. { 2- [3- (4-methoxy-3-methylbenzyl) -3H-imidazol-4-yl] ethoxy} -3,4-dihydro-2H-naphthalen-1 -one; 4- ( { 5- [2- ( { 5-Oxo-1 - [(2-pyridinylsulfonyl) methyl] -5,6,7,8-tetrahydro-2-naphthalenyl}. Oxy) ethyl] -1 H-imidazol-1-yl.} Met.l) -benzon.tp lo; Y 4- ( { 5- [2- ( { 1 [(lsopropylsulfonyl) methyl] -5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl}. Oxy) ethyl] -1 H -imidazol-1 -yl.} methyl) benzonitri io. 20. The compound according to claim 1, characterized in that it is 4- (. {5- [2- (. {5-Oxo-1 - [(2-pyridinylsulfonyl) methyl] -5,6,7, 8-tetrahydro-2-naphthalenyl}. Oxy) ethyl] -1 H -imidazol-1-yl.] Methyl) -benzonitrile or 4- (. {5- [2- ( { 1 - [( I sopropil sulf onyl) methyI] -5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl}. Oxy) ethyl] -1 H -imidazol-1-yl] methyl) benzonitrile. twenty-one . A pharmaceutical composition, characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable carrier, excipient or diluent. 22. The method for treating or preventing restenosis or atherosclerosis, the method, characterized in that it comprises administering to a patient having restenosis or atherosclerosis or the danger of having restenosis or atherosclerosis a therapeutically effective amount of a compound according to claim 1. 23. The method for treating cancer, the method is characterized in that it comprises administering to a patient having cancer a therapeutically effective amount of a compound according to claim 1.